January 13, 2014

The diabetes drug metformin is also being tested in numerous clinical trials for treating different cancers, and several studies point to its apparent activation of a molecular regulator of cell metabolism called AMPK to suppress tumor growth.

But new research appearing the week of Jan. 13 in Proceedings of the National Academy of Sciences (PNAS) suggests that activation of AMPK may actually fuel cancer growth. Researchers from Cincinnati Children's Hospital Medical Center who led the study also recommend that clinicians testing metformin for cancer treatment consider a careful re-evaluation of their clinical data.

The researchers report on extensive laboratory tests that conclude metformin does stop cancer, although not by activating AMPK. Instead, in tests involving glioma brain cancer cells, the authors found that metformin inhibits a different molecule called mammalian target of rapamycin (mTOR) that has been linked to many other cancers.

In the body, metformin also suppresses the actions of insulin and insulin-like growth factors – two molecules that support cancer growth – and also likely independent of AMPK, according to Biplab Dasgupta, PhD, principal investigator and a researcher in the Division of Hematology/Oncology at Cincinnati Children's.

"Our findings do not suggest that clinical trials using metformin should be stopped. Metformin appears to be a very useful drug, but the drug's mechanism of cancer suppression is not clear," Dr. Dasgupta said. "However, our findings unveil a potential role for AMPK as a tumor growth supporter, not a suppressor, in the type of cancer that we study. This is why clinicians using metformin in clinical trials should use caution during data interpretation."

Dasgupta and his research colleagues decided to tackle the question of metformin's anti-cancer properties because some studies point to AMPK as a tumor suppressor, while others have suggested it can promote tumor growth. Ultimately, an accurate understanding of AMPK's role – and how a drug like metformin does stop cancer – will likely be important to continued improvement of targeted cancer therapies, he said.

AMPK is a metabolic enzyme that acts as a key sensor of energy levels in cells. It controls a number of metabolic pathways that allow cells to regulate their energy usage and survival under physiological stress. Cancer cells modify their metabolism to maintain their growth and survival in the stressful environment of the tumor.

To determine how AMPK and metformin react in the context of cancer, the researchers conducted tests using glioblastoma, a highly lethal brain cancer with no cure. Their experiments involved laboratory cell cultures of human glioblastoma cells and glioblastoma tumors transplanted in mice to obtain results in a living organism.

Compared to normal human and mouse tissue, the researchers found that AMPK was highly active in human and mouse glioblastoma cells. This led them to question whether the anti-cancer properties of metformin were independent of AMPK, and instead directed to other molecular pathways.

The researchers then treated human glioblastoma cells with metformin and conducted a series of genetic tests to determine the molecular pathways it uses to stop the cancer growth. Those tests showed clearly that metformin directly inhibited the mTOR pathway (and the cancer) by promoting the interaction of two upstream molecules that stop the pathway's function.

To further verify that AMPK activation by metformin is not involved in stopping the growth of cancer, the researchers also treated the glioblastoma cells with a more specific AMPK activating compound called A769662 that directly binds to AMPK. The treatment did not kill glioblastoma cells, according to the authors.

Dasgupta and his colleagues are continuing their research by testing direct genetic inhibition of AMPK to see how it impacts human glioblastoma cells. Although that research still has to be completed and the results verified, he said preliminary indications are that blocking AMPK appears to kill a significant number of the glioblastoma cells.

Related Stories

Results of some preclinical trials have shown that low doses of the antidiabetic drug metformin may effectively destroy cancer stem cells, a group of cells that are considered to be responsible for tumor initiation and, because ...

Researchers at McGill University have discovered that a key regulator of energy metabolism in cancer cells known as the AMP-activated protein kinase (AMPK) may play a crucial role in restricting cancer cell growth. AMPK acts ...

Adenosine-5'-triphosphate (ATP) is the main energy source for all forms of work inside our cells. Scientists from the University of Helsinki, Finland, have found that even a short-term shortage of ATP supply can be fatal ...

Treating aggressive lung cancer with the diabetes drug metformin along with radiation and chemotherapy may slow tumor growth and recurrence, suggests new preliminary findings from researchers at the Perelman School of Medicine ...

A University of Colorado Cancer Center study published online this month in the journal Cell Cycle shows that breast cancer cell growth, motility and aggression is promoted by excess glucose, as experienced by patients with ...

Recommended for you

Researchers have identified a new mechanism that the tumor suppressor protein p53 uses to trigger cell death via apoptosis and have shown how the process could be harnessed to kill cancer cells. St. Jude Children's Research ...

Strange rings of DNA that exist outside chromosomes are distinct to the cell types that mistakenly produced them, researchers have discovered. The finding raises the tantalizing possibility that the rings could be used as ...

Resveratrol, a chemical found in red grapes, is more effective in smaller doses at preventing bowel cancer in mice than high doses, according to new research published today in the journal Science Translational Medicine.

In industrialized countries like in Europe, acute lymphoblastic leukemia is the most common form of cancer in children. An international research consortium lead by pediatric oncologists from the Universities of Zurich and ...

Use of gene therapy to deliver a protein that suppresses the development of female reproductive organs may improve the survival of patients with ovarian cancer that has recurred after chemotherapy, which happens 70 percent ...

0 comments

Please sign in to add a comment.
Registration is free, and takes less than a minute.
Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.